Since the emergence of human immunodeficiency virus (HIV) in the 1980s it has been assumed that exploration and exploitation of remote natural resources and increases in world travel would result in further pandemics of new and dangerous viral pathogens. Filoviruses, the severe acute respiratory syndrome- coronavirus (Sars-CoV) and the Henipavirus genus of paramyxoviruses are all examples of such agents. Fortunately all have failed to demonstrate the transmissibility or animal reservoirs required to become true pandemics. However, new viruses emerge with regularity and bioweaponization provides the added threat of existing viruses being altered to enhance their pathogenicity or transmissibility. Currently little defense exists in terms of drugs that can be used to treat a wide range of viruses especially uncharacterized ones. Thus, rapid responses to new or changing pandemic threats would be greatly helped by an arsenal of antiviral drugs with overlapping therapeutic indications. One method of doing that is to target common host mechanisms utilized by many viruses to produce a small panel of such drugs. We propose to develop one such target, inhibitors of host cell proteases involved in the processing of viral glycoproteins. Viral glycoproteins and systems vary widely. However, we and others have demonstrated that a whole class of viruses from different families, including Ebola virus and Nipah, all utilize a single class of host factor, endosomal cathepsins, that can be targeted by individual inhibitors. The compounds we develop will be active against the NIAID category A priority pathogens Ebola virus and Marburg virus, and the category C agent SARS-CoV as well as the viral hemorrhagic fever viruses Nipah and Hendra. In addition, the compounds will have broad activity against additional human coronaviruses such as 229E, and reoviruses. Finally, these compounds may well be active against a number of parasitic infections that encode their own versions of cysteine proteases. No effective therapeutic agents exist for any of these viruses, despite their potential to emerge as epidemic pathogens or be utilized as bioweapons. Initial screens of protease inhibitor libraries have yielded promising lead compounds, one of which is being developed by members of our consortium as a therapeutic agent for Chagas disease. We propose to refine these compounds in order to increase their drug-like properties and optimize their activity against the target viruses. The physical, biochemical, and drug-like properties of our initial lead compound, K777, will be optimized via reiterative medicinal chemistry to produce panels for in vitro testing. The best candidates will be selected for further refinement until appropriate candidates for further development are determined. We will perform escape mutant selection to determine how easily virus escapes from these drugs and in what form. In summary, we hope to develop a novel class of inhibitors targeting a specific host cell factor required by a range of different emerging viruses, many of which are potential bioweapon threats.